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Despite advances in the constraint-based framework for genome-scale metabolic modeling, we lack reliable proxies for metabolite concentrations that can be efficiently determined and that allow us to investigate the relationship between metabolite concentrations in specific metabolic states in the absence of measurements. Here, we introduce a constraint-based approach, the flux-sum coupling analysis (FSCA), which facilitates the study of the interdependencies between metabolite concentrations by determining coupling relationships based on the flux-sum of metabolites. Application of FSCA on metabolic models of <jats:italic>Escherichia coli<\/jats:italic>, <jats:italic>Saccharomyces cerevisiae<\/jats:italic>, and <jats:italic>Arabidopsis thaliana<\/jats:italic> showed that the three coupling relationships are present in all models and pinpointed similarities in coupled metabolite pairs. Using the available concentration measurements of <jats:italic>E. coli<\/jats:italic> metabolites, we demonstrated that the coupling relationships identified by FSCA can capture the qualitative associations between metabolite concentrations and that flux-sum is a reliable proxy for metabolite concentration. Therefore, FSCA provides a novel tool for exploring and understanding the intricate interdependencies between the metabolite concentrations, advancing the understanding of metabolic regulation, and improving flux-centered systems biology approaches.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012972","type":"journal-article","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T21:35:04Z","timestamp":1744061704000},"page":"e1012972","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Flux-sum coupling analysis of metabolic network models"],"prefix":"10.1371","volume":"21","author":[{"given":"Mihriban","family":"Seyis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5513-4677","authenticated-orcid":true,"given":"Zahra","family":"Razaghi-Moghadam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoran","family":"Nikoloski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,7]]},"reference":[{"issue":"2","key":"pcbi.1012972.ref001","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nrg3643","article-title":"Constraint-based models predict metabolic and associated cellular functions","volume":"15","author":"A Bordbar","year":"2014","journal-title":"Nat Rev Genet"},{"issue":"3","key":"pcbi.1012972.ref002","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1104\/pp.18.01273","article-title":"Computational approaches to design and test plant synthetic metabolic pathways","volume":"179","author":"A K\u00fcken","year":"2019","journal-title":"Plant Physiol"},{"issue":"13","key":"pcbi.1012972.ref003","doi-asserted-by":"crossref","first-page":"eabl6962","DOI":"10.1126\/sciadv.abl6962","article-title":"The hidden simplicity of metabolic networks is revealed by multireaction dependencies","volume":"8","author":"A K\u00fcken","year":"2022","journal-title":"Sci Adv"},{"issue":"5","key":"pcbi.1012972.ref004","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1529\/biophysj.106.093138","article-title":"Thermodynamics-based metabolic flux analysis","volume":"92","author":"CS Henry","year":"2007","journal-title":"Biophys J"},{"key":"pcbi.1012972.ref005","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4613-1161-4","volume-title":"The regulation of cellular systems","author":"R Heinrich","year":"1996"},{"issue":"10","key":"pcbi.1012972.ref006","doi-asserted-by":"crossref","first-page":"e16879","DOI":"10.1111\/mec.16879","article-title":"Models and molecular mechanisms for trade-offs in the context of metabolism","volume":"33","author":"S Hashemi","year":"2024","journal-title":"Mol Ecol"},{"issue":"2","key":"pcbi.1012972.ref007","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1101\/gr.1926504","article-title":"Flux coupling analysis of genome-scale metabolic network reconstructions","volume":"14","author":"AP Burgard","year":"2004","journal-title":"Genome Res"},{"issue":"34","key":"pcbi.1012972.ref008","doi-asserted-by":"crossref","first-page":"13638","DOI":"10.1073\/pnas.0703262104","article-title":"Metabolite essentiality elucidates robustness of Escherichia coli metabolism","volume":"104","author":"P-J Kim","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pcbi.1012972.ref009","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1104\/pp.114.245787","article-title":"Assessing the metabolic impact of nitrogen availability using a compartmentalized maize leaf genome-scale model","volume":"166","author":"M Simons","year":"2014","journal-title":"Plant Physiol"},{"issue":"1","key":"pcbi.1012972.ref010","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.tibtech.2012.10.011","article-title":"Network analysis: tackling complex data to study plant metabolism","volume":"31","author":"D Toubiana","year":"2013","journal-title":"Trends Biotechnol"},{"key":"pcbi.1012972.ref011","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/1752-0509-3-117","article-title":"Flux-sum analysis: a metabolite-centric approach for understanding the metabolic network","volume":"3","author":"BKS Chung","year":"2009","journal-title":"BMC Syst Biol"},{"key":"pcbi.1012972.ref012","unstructured":"Tian M. 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